The role of the lymphatic system in the absorption and distribution of free or liposome-entrapped antitumor agents, and monoclonal antibodies administered by iv, ip or sc routes in mice, rats and tumor-bearing guinea pigs and nonhuman primates is under investigation. Nonhuman primates bearing DENA-induced hepatocellular carcinomas have been used to compare the plasma clearance, tissue distribution (including uptake by tumor tissue), metabolism and excretion of free and liposome-entrapped cytosine arabinoside (ara-C). In mice, subcutaneous injection of radiolabeled monoclonal antibodies against normal cell types resulted in accumulation of radioactivity in regional lymph nodes to levels 600-fold higher than could be achieved by intravenous administration of the same antibody. Variables such as antibody dose, injection volume, injection site and concentration of carrier protein were studied in order to optimize lymph node uptake of antibody. Early lymph node metastases in guinea pigs of a dermal hepatocarcinoma that could not be imaged scintigraphically with a radiolabeled tumor-specific antibody injected intravenously were, however, clearly demonstrated after interstital injection of the same antibody. The lymphatic absorption and distribution of radionuclides, toxins or chemotherapeutic agents attached to antibodies and adminstered by iv and sv routes is also under investigation. The therapeutic effects of antibody attached to I-131 are being evaluated in hepatocarcinoma-bearing guinea pigs. Conjugation of antibodies to liposomes increased their lymph node uptake by 3-fold in mice given the liposome-antibody conjugates by sc injection.